Research Summary

The gut microbiota, the collection of trillions of commensals colonizing the gastrointestinal tract, does not elicit a pathologic immune response in healthy hosts even though immune cells are constantly in contact with microbial antigens at the mucosal surfaces. This phenomenon is partly due to the fact that the human gut microbiota and immune system have co-evolved for millennia with the host. Diet and environmental influences that have shaped these processes in the past are very different in today’s societies. Recent changes in the gut microbial community composition are thought to contribute to metabolic and immune-mediated diseases. An emerging theme in autoimmunity research is that outgrowth of detrimental commensals (“pathobionts”) or loss of beneficial commensals (“symbionts”) unleashes the autoimmune process in a genetically susceptible host by various mechanisms. While evidence exists for this paradigm in some mouse models, the proof in human autoimmune diseases is still outstanding. A major aim of this laboratory is to characterize the gastrointestinal microbiome of both mice and humans with systemic autoimmune diseases, and to potentially prove causal relations with humanized gnotobiotic animals. The ultimate goal is to develop novel biomarkers and therapeutic strategies for human autoimmune diseases.

Extensive Research Description

We are broadly interested in the role of commensal organisms in the development of autoimmunity. A major question in the lab is whether an autoimmune-prone host that is persistently colonized with cross-reactive commensals, develops chronic autoimmunity via molecular mimicry. We address this hypothesis using the antiphospholipid syndrome as a model disease since the structure and antigenic epitopes are well characterized for the major autoantigen and infectious triggers have been implicated in the pathogenesis. We are also exploring whether prokaryotic commensal protein orthologs can trigger autoreactivity in systemic lupus erythematosus. We study both human samples in vitro and autoimmune murine models in vivo.

In this context, we are currently characterizing the commensal- and autoepitope-specific CD4+ T and B cell responses using synthetic peptides, recombinant fusion proteins as well as protein extracts from cultured anaerobic commensal candidates. We are further applying 16S rRNA-based realtime PCR and next-generation sequencing approaches in order to identify novel candidates. The mouse models we use include the lupus-prone (NZWxBXSB)F1 hybrid and Toll-like receptor 7 transgenic mice. We simultaneously study two knock-out mouse models of autoimmunity that we have crossed to the lupus-prone strains. We eventually plan to merge both human and mouse studies in humanized, gnotobiotic animals that are colonized with human microbiota, taking advantage of the newly established gnotobiotic facility at Yale.

Another research avenue is the effect of genetic variants of the host immune system on the composition and function of the gut microbiome. We are exploring a particular autoimmunity-predisposing single nucleotide polymorphism and its impact on gut microbial community structures. Similar approaches as above will be employed to dissect the host-microbe interactions under the influence of genetic variants.

A third interest in the lab is the impact of dietary components on the autoimmune gut microbiome. We are actively pursuing studies that address the potential protective effects of certain diets in lupus- and antiphospholipid syndrome-prone mouse models. Caloric restriction is another intervention that we plan to explore with regards to its effects on the gut microbiota. This intervention has previously been shown to be protective in a variety of autoimmune models but the impact on the microbiome is unexplored. We plan to elucidate the contribution of the gut microbiota and differentiate it from direct host effects. These efforts should lead to the development of more selective therapeutic avenues that are targeting specifically the gut microbiota.

Lastly, we are studying endogenous retroviruses and their interactions with the gut microbiota in systemic autoimmunity. We use RT-PCR-based strategies to detect and quantify endogenous retroviruses in various contexts and couple these studies with microbiome research detailed above.

In summary, the overarching goal of our research is to discover causal factors within the gut microbiomes of autoimmune-prone individuals, to better understand gut microbial interactions with the host and environmental components, and to manipulate gut microbial communities as a novel therapeutic approach in autoimmunity.

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Cladogram generated from IgA-Seq data of patients with antiphospholipid syndrome and control subjects.

Cartoon depicting how diet affects the gut microbial community composition that in turn modulates immune cell functions. The microbiota effects on adaptive immunity lead to autoimmune and thrombotic complications in lupus and antiphospholipid syndrome.

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